Renal disease is a general term, which describes a class of conditions in which the kidneys fail to filter and remove waste products from the blood. There are two forms of renal disease; acute kidney injury (AKI) and chronic kidney disease (CKD). CKD is usually asymptomatic, except in its most advanced state. Consequently, blood and/or urine tests generally are required to make a diagnosis.
The definition of CKD developed by the Kidney Disease Outcomes Quality Initiative (KDOQI) was:                1. Kidney damage present for at least 3 months, as defined by structural or functional abnormalities (most often based on increased albuminuria e.g. urinary albumin/creatinine ratio [UACR]≥30 mg/g) and/or        2. Glomerular filtration rate (GFR)<60 mL/min/1.73 m2 present for at least 3 months.        
Within this framework, KDOQI then classified CKD into five stages, as follows:                Stage 1: Kidney damage with GFR 90 mL/min/1.73 m2.        Stage 2: Kidney damage with GFR 60-89 mL/min/1.73 m2.        Stage 3: GFR 30-59 mL/min/1.73 m2.        Stage 4: GFR 15-29 mL/min/1.73 m2.        Stage 5: GFR<15 mL/min/1.73 m2 or kidney failure treated by dialysis or transplantation.        
In the United States, based on data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) study, an estimated 11.1 percent (22.4 million) of adults aged 20 or older have CKD stages 1-3. An additional 0.8 million U.S. adults aged 20 or older have CKD stage 4, and more than 0.3 million have stage 5 CKD and receive hemodialysis.
Analyses of NHANES data between 1988-1994 and 1999-2004 suggest that the prevalence of CKD is rising for every CKD stage, but with a particular increase in the prevalence of individuals classified with CKD stage 3. The number of patients with stage 5 CKD requiring dialysis also has increased. It has been estimated that more than 700,000 individuals will have End Stage Renal Disease (ESRD) by 2015.
Although CKD can be caused by primary kidney disease (e.g. glomerular diseases, tubulointerstitial diseases, obstruction, and polycystic kidney disease), in the vast majority of patients with CKD, the kidney damage is associated with other medical conditions such as diabetes and hypertension. In 2008, excluding those with ESRD, 48 percent of Medicare patients with CKD had diabetes, 91 percent had hypertension, and 46 percent had atherosclerotic heart disease. Other risk factors for CKD include age, obesity, family history, and ethnicity.
CKD has been associated with numerous adverse health outcomes. Many studies have reported that a GFR of 30-59 mL/min/1.73 m2 is associated with an increased risk of mortality, cardiovascular disease, fractures, bone loss, infections, cognitive impairment, and frailty. Similarly, there appears to be a graded relationship between the severity of proteinuria or albuminuria and adverse health outcomes, including mortality, ESRD, and cardiovascular disease. Further, the risk for adverse outcomes conferred by reduced GFR and increased albuminuria (or proteinuria) appears to be independent and multiplicative.
The rationale for considering screening for early-stage CKD includes the high and rising prevalence of CKD, its known risk factors, its numerous adverse health consequences, its long asymptomatic phase, the availability of potential screening tests for CKD, and the availability of treatments that may alter the course of early-stage CKD and reduce complications of early-stage CKD or its associated health conditions.
Some organizations already recommend CKD screening in selected populations. Kidney Disease: Improving Global Outcomes (KDIGO) recommends screening of all patients with hypertension, diabetes, or cardiovascular disease. The American Diabetes Association recommends annual screening of all adults with diabetes, based on “expert consensus or clinical experience.” The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) recommends annual screening of all patients with combined hypertension and diabetes. Also advocating selected screening, the National Kidney Foundation sponsors free CKD screening for all adults with hypertension, diabetes, or a primary relative with a history of kidney disease, hypertension, or diabetes.
In most patients with CKD stages 1-3 GFR declines slowly. However, the rate of decline varies among individuals, and many factors appear to impact progression. Because CKD stages 1-3 usually progress asymptomatically, detection of early-stage CKD requires laboratory testing.
Some organizations recommend monitoring for changes in kidney function or damage in patients with CKD. For example, the Kidney Disease Outcomes Quality Initiative (KDOQI) recommends at least annual estimated GFR measurement in adults with CKD in order to predict onset of ESRD and evaluate the effect of CKD treatments. JNC7 recommends annual quantitative measurement of albuminuria in all patients with “kidney disease.” KDOQI also recommends more frequent monitoring of CKD patients with worsening kidney function.
The appearance in the blood of cellular proteins released after tissue injury is gaining more and more interest as being important in the management of patients with tissue injury due to acute ischemia/reperfusion, neurological disorders, cancer, organ rejection or trauma. Fatty acid-binding protein (FABP) is one such tissue injury biomarker. It is a relatively small cytoplasmic protein (15 kDa), which is abundantly expressed in tissues with an active fatty acid metabolism e.g. heart and liver. Nine distinct types of FABP have now been identified and each type exhibits a characteristic pattern of tissue distribution. They were named according to the tissue in which they were first discovered and include liver-type (L-FABP/FABP1), intestinal-type (I-FABP/FABP2), muscle and heart-type (H-FABP/FABP3), adipocyte-type (A-FABP/FABP4), epidermal-type (E-FABP/FABP5), ileal-type (I-FABP/FABP6), brain-type (B-FABP/FABP7), myelin-type (M-FABP/FABP8) and testis-type (T-FABP/FABP9).
FABPs bind long chain fatty acids (FA) with high affinity. Their tertiary structure incorporates a slightly elliptical beta-barrel linked to a helix-turn-helix motif, thought to act as a portal for FA access and egress. Their primary function is the facilitation of intracellular long-chain fatty acid transport, while other functions include regulation of gene expression by mediating fatty acid signal translocation to peroxisome proliferator activated receptors (PPARs).
FABP1 is expressed in the proximal tubules of the kidney, liver, intestine, pancreas, lung and stomach. It has been hypothesized to be involved in lipid absorption by the enterocyte and in hepatocyte lipid transport and lipoprotein metabolism. Its unique binding and surface characteristics are likely to contribute to its specific functional properties. In contrast to the stoichiometric binding of long-chain FA by other FABPs, each FABP1 molecule binds two FA molecules. It also binds a variety of other small hydrophobic ligands such as lysophospholipids, heme and vitamin K.
U.S. Pat. No. 7,592,148 B1 discloses a method for diagnosis or prognosis of kidney disease in humans, which comprises detecting FABP1 in kidney tissue or urine. Kamijo et al. (Diabetes Care 2011; 34:691-6) employed the CMIC ELISA to demonstrate that urinary excretion of FABP1 increases with the deterioration of renal function, while serum FABP1 was not significantly affected. These methods teach the determination of FABP1 in urine as the sample matrix. The CMIC ELISA is commercially available for urine analysis of FABP1. U.S. Pat. No. 7,592,148 B1 reports the analysis of 34 urine specimens, collected from patients with CKD. In addition, the amount of NAG (N-acetyl-β-D-glucosaminidase) in the urine specimens was also determined. NAG is a marker enzyme existing in kidney tissue cells and the level of NAG in urine is generally considered as an indicator for kidney tissue injury. It was confirmed that the level of NAG and that of FABP1 positively correlate with each other in standard cases. However, in 15% of cases, although the level of NAG was high, the level of FABP was low. It was suggested that, in this group, the level of FABP1 in kidney tissues is low. However, it might also be postulated that the low level of FABP1 in these samples may be due to the nature of the disease in these particular patients, which results in a reduction in the amount of FABP1 leaked into the urine.
There is scientific literature to suggest that the findings of the publication by Kamijo et al have not been consistent with work done by other groups. Kim S S et al. (Diab Res Clin Pract, 2012) found that FABP1 was not significantly elevated in the urine of patients with microalbuminuria. Furthermore they found that many of the urine samples were below the detectable cut off range of the CMIC ELISA used in the study. Kamijo et al (2006) indicate the use of serum FABP1 as not being an effective biomarker for kidney disease as the source of FABP1 can also originate from liver tissue damage. This would naturally lead others to ignoring the utility in measuring serum levels of FABP1 to aid the diagnosis of renal disease.
Despite the importance of measuring clinical parameters for CKD in serum or urine, there are few diagnostic tests to predict and monitor the progression of this disease. Measurement of GFR is not sufficiently sensitive for early detection of kidney disease, while the measurement of urinary protein is not specific for kidney disease, nor is it suitable for monitoring the progression of the disease. Therefore, there is a requirement for a specific and sensitive clinical marker for the diagnosis of early CKD and staging of renal disease.